It is well known that the dissolution rate of an orally ingested drug in the human alimentary canal can greatly effect the physiologic effect and biological activity of the drug, particularly where the rate of dissolution is slower than the rate of absorption of the drug in the body, i.e. the absorption of the drug is dissolution rate-limited. In cases other than dissolution rate-limited absorption, the rate of dissolution is not so important in this respect, since the body is then receiving the dissolved drug as fast as it can use it.
Since the rate of dissolution of the drug is important, it has also become important to be able to measure this rate accurately, reproducibly and, in a manner which correlates with dissolution of the drug in the body cavity in which it is normally to be dissolved during treatment of a patient. The latter property is commonly referred to as correlation between in vitro and in vivo dissolution.
Flexibility of the apparatus and method are also significant, in that they are preferably applicable to a wide range of drug products. Simplicity is also highly desirable, since the mechanism should be relatively easy to operate and not require an undue amount of time in setting up to perform the test. It is also desirable, if possible, to provide an apparatus and method which are compatible with automation, at least in some uses of the apparatus.
Such dissolution methods and apparatus may be important in assuring that drug products meet certain requirements of the Federal Drug Administration (FDA) with regard to rate of dissolution. For example, if a drug producer advertises that a drug unit (pill, pellet, capsule, etc.) of his product contains Q grams of active ingredient, then the FDA may, for example, require that 75% of the stated amount Q be dissolved within 30 minutes of ingestion. Obviously, this is very difficult or impossible to measure in vivo, for example in a patient's stomach, and therefore some universally accepted test equipment and procedure must be provided which is accepted as correlating sufficiently well with the in vivo condition to provide a useful representation of actual in vivo dissolution rates.
For over twenty years a large variety of methods and apparatus have been proposed and tested for accomplishing such standardized measurement of dissolution rate. In general, these involve methods of agitating a solvent bath in which the drug dosage object is placed; lacking such agitation, the dissolved material will move away from the surface of the underlying dosage object only very slowly, thus maintaining a high concentration of the dissolved drug adjacent the surface of the object and thereby inhibiting the rate of further dissolution. The dissolution medium or solvent usually consist of purified water, USP, or a specific buffer system, or a specific mixture of solvents. If the dosage unit were stationary in vivo, it would not be necessary to provide agitation in the test apparatus. However, obviously the dosage object will be subjected to substantial agitation and motion in vivo, and to correlate with the in vivo conditions the in vitro tests should provide some kind of equivalent relative motion between the dosage object and the solvent bath.
The general type of equipment which has been used in the past comprises a container in which the solvent material (dissolution medium) is placed and in which the drug dosage unit is immersed, while some type of agitation is applied. Samples of the solvent are then taken at appropriate times and positions in the bath and the concentrations of the drug present in the solvent determined, as by spectrophotometer measurements. From these results, the percentage of drug dissolved at any given time is calculated. Currently, the FDA has issued monographs which specify the acceptable limits on the range of results obtained in such measurements in specified types of standard test equipment, and at least in some cases specify also the maximum permitted standard deviation for the results of a large number of such tests on any given equipment with a specified procedure.
In some prior-art apparatus for conducting such tests, the dosage unit is placed in a solvent bath in a container which may have a flat or a curved bottom, and the liquid agitated as by a rotating paddle, for example. In order to constrain the geometric position of the dosage unit during agitation, in some cases the dosage unit was placed in a suitable small porous basket; this is particularly desirable where the dosage unit may float, as in the case of certain capsules. Such a basket arrangement has been utilized with an adjacent rotating paddle to provide the agitation, and in some cases the basket has been secured to a vertical rotating rod so as to rotate on the axis of the rod, or secured to a fixed arm extending at right angles to the rod, the entire basket then swinging or orbiting around the axis of the rod as the rod is rotated.
All previously proposed methods and apparatus for accomplishing such measurements of dissolution rate are subject to criticism on the grounds of failure to meet one or more of the above-identified criteria to the extent which might be desirable. Thus while they may have been acceptable for some purposes, each of them has one or more drawbacks or limitations in the respects noted.
At present, there are two standardized types of test equipment which are used for such purposes, known as USP I and USP II. USP I uses a porous wire-mesh basket of cylindrical shape which contains the dosage unit to be tested, and which is clipped to the lower end of a vertical rotating rod with its cylindrical axis coaxial with the axis of the rod. The rod and basket are rotated at a predetermined rate, and other parameters of the test apparatus and method are as specified in detail by the U.S. Government standard, namely the United States Pharmacopeia XXI, the National Formulary XVI, 1985.
In the USP II apparatus the dosage unit is allowed to sink to the bottom of the container, and the paddle rotates in a horizontal plane, driven by a vertical drive shaft located above the dosage unit, which is preferably lying on the bottom of a concave-upward lower face of the container. This standard procedure is also set forth in the above-identified standards publication.
While each of the above described USP methods and apparatus has provided usable results, it would be desirable to be able to obtain higher rates of dissolution for a given speed of rotation of the vertical shaft. For example, typically the specifications for a test of a particular dosage material using USP I or USP II will call for one-hundred revolutions per minute (RPM) of the drive shaft for the agitator, whether it rotates a paddle or a basket. This is in order to obtain agitation sufficient to produce the specified percentage of dissolution within a reasonable length of time. However, such relatively high rates of rotation introduce problems of resultant uncontrolled mechanical vibrations, which may influence the dissolution rate, as well as flow characteristics in the solvent which may be so violent as not to be accurately reproducible. In general, it is believed to be desirable to be able to produce a given rate of dissolution with as slow a speed of rotation as possible, not only from the above-described viewpoints but also from the viewpoint that the conditions thereby produced at the dosage unit would appear to correlate more closely with the relatively slow motions to which the dosage unit is typically subjected in vivo.
It is also generally important that the dosage unit, when in the process of dissolution, does not stick to its container, since otherwise all surfaces will not be equally exposed to the solvent.
Accordingly, it is an object of the present invention to provide a new and useful method and apparatus for the controlled dissolution of a pharmicalogical dosage unit.
Another object is to provide such method and apparatus in which a high rate of dissolution is obtained for a relatively low rate of rotation of the agitating system.
A further object is to provide such method and apparatus which also minimizes the possibilities that the dosage unit may stick to the receptacle in which it is contained and thus not be exposed equally on all surfaces to the solvent material.